Inhalation has become the primary route of administration in the treatment of asthma. This is because, in addition to providing direct access to the lungs, medication delivered through the respiratory tract provides rapid and predictable onset of action and requires lower dosages compared to the oral route.
Pressurised metered dose inhalers (pMDIs) are currently the most commonly used inhalation devices. Such devices comprise a canister containing a suspension of fine drug particles in a propellant gas. Upon actuation, the aerosol contents are expelled, through a metering valve, and a metered dose is propelled into the lungs of the patient. The biggest threat to the continued use of pMDIs is that they rely on propellants, namely chlorofluorocarbons (CFCs), which have been implicated in the depletion of the ozone layer.
Several types of dry powder inhalers (DPIs) have been developed, in which the inhalation air of the patient is used for dispersing the drug particles. DPIs are user friendly, as they do not require coordination between actuation and inspiration. The powdered medicament is arranged as unit dose containers. e.g. blister packs, cartridges or peelable strips, which are opened in an opening station of the device. Alternatively, the unit dose is measured from a powder reservoir by means of a metering member, e.g. a dosing cup.
To increase flowability and dosing accuracy of the powdered medicament, the fine drug particles of respirable size are typically mixed with coarser carrier particles to form an ordered mixture, wherein line drug particles are attached to the larger carrier particles. This technique complicates the powder aerosolization process and, in particular, necessitates the break-up of the drug/carrier agglomerates before they enter the patient's mouth and throat, where individual large particles and agglomerated large and small particles tend to deposit. Effective aerosolization and deagglomeration of the powder requires that forces exerted on particles (be they on exposed surfaces of the device, between drug and carrier particles or between drug and drug particles) must be overcome under all expected inhalation profiles.
The aim of the inhaler devices is to produce a high Fine Particle Dose (FPD) of particles in the respirable size range. However, the ability of a device to aerosolize and deagglomerate the drug particles into a respirable particle size range depends on the patient's inspiration technique for most DPIs currently available. An ideal dry powder inhaler would provide uniform powder aerosolization and deagglomeration over a wide range of inhalation profiles, so as to generate consistent doses of respirable particles in the final dispersion.
Various techniques have been used in DPIs to aerosolize and deagglomerate drug powder during inhalation. These include turbines and impellers (e.g. U.S. Pat. Nos. 4,524,769, 3,831,606 and 5,327,883) or other mechanical means (WO 98/26828), compressed gas (e.g. U.S. Pat. No. 5,113,855, 5,349,947 and 5,875,776), cyclones (e.g. U.S. Pat. No. 5,301,666 and WO 99/07426), electrostatic suspension and piezoelectric vibration (e.g. U.S. Pat. No. 3,948,264 and WO 97/26934), venturis (U.S. Pat. Nos. 4,200,099, 4,240,418 and WO 92/00771) and impactors (U.S. Pat. No. 5,724,959). Several patents have used electronic or other means of sensing of the airflow or pressure drop through the device to trigger the release of drug particles into the airstream so as to coordinate activation of release and inhalation (e.g. WO 93/03782, WO 97/20589 and U.S. Pat. No. 5,388,572) or a means to mechanically control the patient's inspiration rate (U.S. Pat. Nos. 5,727,546 and 5,161,524). In general, these DPIs have become more complicated and expensive.
Flow behavior in a DPI is critical for the aerosolization and particle break-up processes, especially if the device is passive. i.e. has no mechanical or electrical augmentation or triggering mechanisms. In order to maximize the Fine Particle Fraction (FPF) and provide a consistent dose over a wide range of patient inhalation profiles, particular attention should be paid to the levels of turbulence in critical regions where drug-carrier break-up is likely to occur. Therefore, we have performed Computational Fluid Dynamics (CFD calculations on various inhalers to characterize the steady-state flow behaviour of the devices. In a number of dry powder inhalers, inlet air is focused on the dosing cup or holding portion of the metered dose (e.g. WO 99/07426, WO 92/00771 and WO 92/09322) and thus the vast majority of the powder is aerosolized at the very beginning of the inhalation cycle. Typically, the designers of inhalers place importance on immediate aerosolization of powder under the belief that deep lung deposition relies on introduction of aerosol very early in the inhalation cycle. However, tests have concluded that initial aerosolization is typically not a serious issue. Deep lung deposition to targeted sites depends much more strongly on delivering particle doses in the correct size range. Too large particles tend to impact on surfaces in the upper airways due to their high inertia and too small particles tend to reach surfaces due to Brownian diffusion. In fact, even if most of the powder is aerosolized immediately and effectively it tends to be at very low flow velocity conditions and thus low turbulence levels. Thus, when the particles exit the device, there is little turbulent shear energy available for particle deagglomeration and a significant fraction of the dose is thus deposited in the upper airways since they are often still attached to larger carrier particles or exist as large agglomerates.
Based on CFD calculations, a number of deficiencies in known passive inhalers have been identified. These include:
Poor control of flow. Peak velocities, in general, occur slightly downstream of inlets and the jet is focused in the vicinity of the dosing cup. The majority of the pressure drop and highest levels of turbulence occur upstream of the dosing cup, before particles are aerosolized. This is essentially wasted energy that could be used more efficiently downstream of particle dispersion in order to effectively break-up drug/carrier particles. In addition, there are typically significant “dead” zones in and around the dosing cup, which reduces particle aerosolization and thus increases the energy required to disperse particles. Large recirculation zones downstream of the dosing mechanism provide potential sites for particle redeposition.
Uncontrolled turbulence. In current DPIs, turbulence in the outlet free jet is uncontrolled and will be substantially affected by the patient's inhalation technique and mouth geometry. Ultimately, this can lead to significant variation in fine particle fraction from patient to patient even using the same device under identical flow conditions.
Inappropriate release time. Experimental data shows that in present DPIs aerosolization of particles occurs at the initiation of the inhalation cycle, long before the flow is developed and velocities and turbulence reach peak values. To maximize break-up of particles due to turbulence, it is desirable to aerosolize the powder later in the inhalation cycle where turbulence is higher and the flow more developed. This has the additional benefit that powder that is aerosolized in a steady state flow condition is less likely to be redeposited in recirculation zones.
Current passive devices operate in a range where a change in the flow rate or pressure drop across the device (which translates into a change in the turbulence experienced by the aerosols) leads to very significant changes in the aerosol distribution in the patient's lungs. It is more desirable to operate in a range where the aerosol properties are not strongly influenced by the inhalation rate. This, again, implies that aerosolization should occur near maximum turbulence conditions for a low flow rate (pressure drop) peak, such as would occur in an elderly or adolescent patient. Higher flow rates, as would occur in a healthy adult, should not significantly alter the resulting aerosol properties. Thus, sufficient turbulence should be achieved to break-up drug and carrier particles already at low flow rate conditions.